SOHO Plenary Session: Overcoming Resistance to Targeted Therapies in CLL

HOUSTON — As treatments for chronic lymphocytic leukemia (CLL) evolve, new methods and challenges have arisen to address the disease’s resistance to targeted therapies.

Thomas Kipps, MD, PhD, Professor of Medicine at the University of California, San Diego, Moores Cancer Center, spoke about this topic during a plenary session titled “Meeting the Challenge of Resistance to Targeted Therapies in CLL” at the 10th Annual Meeting of the Society of Hematologic Oncology.

A key part of meeting this challenge is understanding the distinct types of CLL, as the type of CLL heavily influences a patient’s prognosis and can inform clinicians about the best potential treatment strategies. The two subtypes of CLL are defined by the mutation status of the immunoglobulin heavy chain variable (IGHV) region genes. The pre-germinal center B-cell type of CLL lacks mutations in IGHV genes, while the post-germinal center B-cell type of CLL has mutations in the IGHV genes.

These two subtypes of CLL are associated with different outcomes, as the unmutated type of CLL typically has a “much more aggressive clinical course” than the mutated type of CLL, Dr. Kipps said.

“There’s a shorter time from diagnosis to therapy [in the unmutated type of CLL], but there’s also a shorter time to progression or relapse after even successful therapy,” he says. “And this has to be borne in mind when looking at the resistance to therapy.”

BTK Inhibitors in CLL: Advantages and Challenges

While continuous therapy with a Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib can “provide prolonged profession-free survival (PFS) independent of IGHV mutation status,” Dr. Kipps said, challenges remain in overcoming patient resistance to BTK inhibitor treatment.

An analysis of data from the RESONATE, RESONATE-2, RESONATE-17, and ILLUMINATE trials identified several risk factors for poor PFS on ibrutinib therapy, Dr. Kipps said. These risk factors include relapse from prior treatments, TP53 mutations, high serum lactate dehydrogenase, and high serum β-2M. Researchers found patients who had none or one of these risk factors had a three-year PFS of 87%, while those with two risk factors had a three-year PFS rate of 74%, and patients with three to four risk factors had a three-year PFS rate of 47%.

“[This] also translates into affecting the overall survival as well, so this has clinical significance,” Dr. Kipps said. “I think we need more algorithms of this sort, to sort out who’s going to benefit from this type of therapy.”

The primary reasons why patients fail to maintain long-term PFS on BTK inhibitors are drug resistance, drug intolerance due to side effects such as atrial fibrillation, and “desire to be free of continuous drug therapy,” he said. Mutations in BTK and/or PLCG2 occur in around 80% of patients who develop “true resistance” to BTK inhibitors, with their lymph node size increasing despite the continuation of therapy, Dr. Kipps said.

However, “it’s fortunate that we have now a selection of newly approved agents other than ibrutinib that we can also select upon,” he said.

Acalabrutinib is one of those agents, Dr. Kipps said, and it may be well tolerated by those who cannot tolerate ibrutinib, and vice versa.

“It’s nice to have a choice, and you should be aware of what the patient is going through,” he emphasized.

There’s also the “new kid on the block,” zanubrutinib, Dr. Kipps said. In an interim analysis of the phase III ALPINE study, which compared zanubrutinib and ibrutinib for patients with relapsed/refractory CLL, the 12-month PFS was superior in patients treated with zanubrutinib. The toxicity and frequency of atrial fibrillation was also lower in the patients treated with zanubrutinib.

It is important to recognize, he said, that there are two types of BTK inhibitors—covalent and non-covalent. Patients who are resistant to BTK inhibitors often have acquired mutations in BTK that prevent a covalent BTK inhibitor from forming a covalent bond with BTK. This means patients with that type of BTK mutation may have cross-resistance to covalent BTK inhibitors but could respond to a non-covalent BTK inhibitor, such as pirtobrutinib.

“The important thing to note is that the overall response rate of patients with the [BTK] mutation 481 versus [patients with] wild-type [BTK] seem to be comparable, so [pirtobrutinib] is fulfilling its bargain to be able to be active in patients who develop this particular BTK mutation,” he said. “One should note this if you have a patient suspected of having resistance to the covalent [BTK] inhibitors.”

Exploring Other Approaches to Overcoming Treatment Resistance in CLL

BCL-2 inhibitors, such as venetoclax, “can actually provide for deep clinical responses and affect clearance of detectable minimal residual disease (MRD) in most patients, particularly when used in combination with anti-CD20 monoclonal antibodies or BTK [inhibitors],” Dr. Kipps said.

However, some patients are resistant to venetoclax, with some of the risk factors for venetoclax resistance including TP53 mutations/del(17p), a complex karyotype, unmutated IGHV, relapse after prior therapy, and high-level expression of ROR1, which can increase as patients progress on venetoclax.

“These are the patients you have to worry about,” he said.

It is important to consider other strategies for patients who cannot clear MRD even with a combination of therapies.

“Rather than just piling on, we should try to think outside the box and look at other strategies. In this case, the [chimeric antigen receptor] T-cell therapy comes to mind,” Dr. Kipps said.

Although much progress has been made, key questions remain, and it is critical to keep working toward therapies to address treatment resistance, he said.

“Further work to define improved therapies for such high-risk patients may allow for improvements in the clinical outcome for all patients,” Dr. Kipps concluded.